268 Integrative Genomics Identifies Evolutionary, Temporal, and Cell-lineage Origin of Hydrocephalus Risk Gene

INTRODUCTION: Our previous work identified MAEL, a gene involved in regulation of DNA transposon activity and histone methylation, as a transcriptome-wide predictor of pediatric hydrocephalus (Hale et al., Cell Reports, 2021). Here we aim to characterize the function of MAEL across timescales and cell-lineages in the developing human brain to understand the pathophysiological basis of hydrocephalus. METHODS: We performed taxonomic analysis of MAEL across species using Ensemble. Analysis of single-cell RNA sequencing (scRNA-seq) of 49 brain regions across the prenatal period from the Developing Human Brain Atlas (Allen Institute) and an atlas of late-prenatal cortical tissue identified temporospatial MAEL expression patterns. Finally, to estimate the degree to which in vitro models recapitulate expression patterns of MAEL in the developing brain, we analyzed scRNA-seq from human neural and choroid-plexus organoids. RESULTS: We performed taxonomic evolutionary gene-mapping to define the evolutionary origin of MAEL to assess suitability for mechanistic characterization in model systems. MAEL is among the top 0.01% human-specific genes and shares < 50% sequence homology with mammalian model organisms. scRNA-seq identified MAEL first detected in the telencephalon at 9 weeks post-conception, highest expressed in the sub-ventricular zone at 16 weeks, and lowest expressed in the hippocampus at 21 weeks post conception. Temporospatial expression of MAEL in the late-prenatal cortex identifies MAEL expression largely restricted to the neural progenitor cells before reaching steady-state expression throughout the cortical layers at 39 weeks gestation. Finally, spatial MAEL expression is largely preserved in brain organoids and robustly expressed in choroid plexus organoids highlighting the utility of these models in future mechanistic studies. CONCLUSIONS: We delineate the evolutionary origin and temporospatial patterns of MAEL expression in the developing human brain and organoid models. These data provide the premise for understanding the detailed molecular-genetic underpinnings of hydrocephalus.